The purpose of this study is to optimize the extraction process and study antioxidant activity of Polysaccharide extracted from Centipeda minima. The Box-Behnken design-response surface methodology was adopted to optimize the extraction process of polysaccharides from Centipeda minima. We purified the crude polysaccharides from Centipeda minima, as well as determined the purity, monosaccharide composition, and molecular weight of the purified fraction. Fourier transform infrared spectrometer (FT-IR) and scanning electron microscopy (SEM) were used to analyze the structural features of the polysaccharides. Further, we investigated the antioxidant activities of different fractions of polysaccharides. Consequently, the results showed that the optimum extraction conditions for polysaccharides were: a liquid-solid ratio of 26 mL/g, extraction temperature of 85.5 °C, and extraction time of 2.4 h. Moreover, the yield of polysaccharides measured under these conditions was close to the predicted value. After purification, we obtained four components of Centipeda minima polysaccharides (CMP). The purity, monosaccharide composition, molecular weight, and structural characteristics of CMP were different, but with similar infrared absorption spectra. CMP exhibited a typical infrared absorption characteristic of a polysaccharide. Besides, CMP displayed good antioxidant activity, with potential to scavenge DPPH radical, hydroxyl radical, and superoxide radical. Therefore, this study provides a reference for future research on the structure and biological activity of CMP, and lays a theoretical foundation for food processing and medicinal development of CMP.